Neuronal function is dependent on ion channels. Changes in ion channel type, localization or structure can have dramatic effects on membrane potential, conduction characteristics and action potential threshold, as well as other functional properties of neurons. The dependence of neurons on ion channel properties implicates ion channels in numerous disorders, and therapeutic treatments, of the nervous system.
Demyelinating diseases are among the most devastating diseases of the nervous system. Myelin is present in both the central and peripheral nervous systems and is largely responsible for fast salutatory conduction of nerve impulses. Demyelinating conditions are characterized by slowed or blocked conduction of nerve impulses, resulting in motor, sensory, autonomic, cognitive and emotional disturbances. Many demyelinating conditions are known, of which the most widely recognized is multiple sclerosis.
Administration of potassium channel blockers can compensate to some extent for demyelination of the axon. Treatment with mono- and/or di-aminopyridines, which are potassium channel blockers, has shown promising results in treatment of multiple sclerosis. However, treatment with a potassium channel blocker can render a neuron hyperexcitable, resulting in undesirable side effects.
There are currently no available therapies for restoring motor function in subjects with chronic spinal cord injury (SCI), a population estimated at 250,000 in the USA alone. Although many pharmaceutical products are used to treat subjects with SCI, these are almost exclusively directed to the amelioration of individual symptoms, such as pain and spasticity or the treatment of dependent conditions, such as pressure sores and bladder infections. Even a treatment with minimal effectiveness might represent a major improvement in the quality of life for subjects with SCI. Literature suggests that clinically significant improvements may be obtained with 4-aminopyridine (4-AP), a K+ channel blocker. (1,2,3,4) However, the use of 4-AP is limited by various side effects associated with central nervous system activation, which include restlessness, confusion, and infrequently reported findings of generalized tonic-clonic seizure (5,6,7).
HP184 (N-[N-propyl]-N-[3-fluoro-4-pyridinyl]-1H-3-methylindole-1-amine hydrochloride) is a sodium and potassium channel blocker. It has demonstrated activity as a voltage dependent blocker of potassium currents in PC12 cells, and as a use- and frequency dependent blocker of sodium channels. (8,9). Use-dependent sodium channel blockers act more effectively during conditions of cellular depolarization. They demonstrate little or no effect on normal neuronal signaling, but enable the blockade of sodium channels during seizures, head trauma, or ischemia. (10) Many of these agents are cerebroprotective in animal models of these pathological conditions.
In a rat compression model of spinal cord injury with mild intensity, HP184 significantly improved motor function (operationally defined as open field walking analysis) when orally administered (3, 10 and 20 mg/kg, po) to rats with an established, (25 day—post injury) spinal cord injury. This improvement was equaled by the improvement observed with 4-AP (0.6 mg/kg, ip). Drugs were administered on days 25, 26 and 27. The baseline walking analysis of the animals, prior to drug administration, showed no statistical differences across groups. Rats were sacrificed on day 30, and spinal cords were removed. Histochemical myelin staining (using Luxol Fast Blue) showed that spinal cords from the vehicle-treated group had extensive myelin loss. HP184 was then tested in a more severe injury paradigm.
In a second study, HP184 (3 mg/kg, po) significantly improved motor function in rats with long-standing (35 day—post injury) spinal cord injury of moderate intensity. Statistically significant improvement in open field walking was observed for HP184 dose groups in both studies described above.
Further, multiple dose studies in moderately injured rats (compression model) have confirmed the effectiveness of once a day oral dosing with HP184 at 3, 1, and 0.3 mg/kg. In summary, HP184 has been shown to be efficacious, as determined by the improvement in walking ability in a rat model of spinal cord injury.
However, even HP184 studies show that therapies such as 4-AP and HP184 are hindered by difficulties with transport of drugs across the blood-brain barrier and blood-nerve barrier in therapeutically effectively doses without undesirable side effects. Additionally, after a relatively small dosage range, it may become necessary to resort to direct, intraventricular delivery of such compounds in larger dosage amounts in order to avoid deleterious side effects.
Thus, there is a continuing need for compositions and methods for regulating ion channels in an individual and for allowing transport of such compositions to neuronal sites in such a manner as to increase the range of possible non-intrathecal dosage deliveries. Even just a small increase in dosage mat means many millions of health costs saved through inexpensive oral or other non-invasive delivery systems and methods.